Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers showing pronounced necroinflammation, abnormal angiogenesis, and extensive fibrosis. As these features are critical for studying the role of the pathologic host microenvironment in tumor initiation, progression, and treatment response, alternative HCC models are desirable. Here, we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of significant hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of murine HCC cell lines requires 30 minutes per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus in Mst1–/–Mst2F/– mice and results in development of HCC tumors (hepatocarcinogenesis) concomitantly to liver cirrhosis.